Raf promotes human herpesvirus-8 (HHV-8/KSHV) infection

Abstract

Human herpesvirus-8 (HHV-8/KSHV) is etiologically associated with Kaposi's sarcoma (KS) and other tumors. Constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway has been associated with a variety of tumors, including AIDS-related KS. The oncoprotein Raf is situated at a pivotal position in regulating the MAPK pathway. Hence, we analysed the effect of oncoprotein Raf on HHV-8 infectious entry into target cells. Here we report Raf expression to significantly enhance HHV-8 infection of target cells. These findings implicate a role for Raf not only in the infectious entry of HHV-8 but also in modulating KS pathogenesis.

Modulation of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by MEK/ERK, JNK, and p38 Multiple Mitogen-Activated Protein Kinase Pathways during Primary Infection

“…The activation of MEK pathway is important for KSHV infection, since specific inhibitors of MEK pathway reduce KSHV infectivity and the expression of KSHV early transcripts without affecting virus binding (38,42). Consistently, overexpression of Raf, a component of MEK pathway, enhances KSHV infectivity at the postattachment stage (1). Recently, it has been shown that binding of KSHV virions to the cells is sufficient to activate the RTA (Orf50) promoter (32).…”

“…Similarly, it has been reported that the MEK MAPK pathway plays an important role in KSHV infection. KSHV activates MEK MAPK pathway at the early stage of primary infection, and the MEK pathway, in turn facilitates KSHV infection at the postattachment stage (1,38,50). Specific inhibitors of MEK MAPK pathway reduce KSHV infectivity, whereas constitutive expression of the upstream kinase Raf enhances KSHV infectivity (1,26).…”

Negative Regulation of the Alpha Interferon-Induced Antiviral Response by the Ras/Raf/MEK Pathway

“…This agrees with a previous report which showed that differential susceptibility between primary and transformed cells in the absence of IFN is not dependent on the MEK-ERK pathway (3). However, several viruses have been reported to be sensitive to U0126 treatment (1,30,39,49,50). For example, inhibition of MEK by U0126 during influenza virus infection resulted in nuclear retention of viral ribonucleoprotein complexes and reduction of viral progeny production (50).…”

Activation of the Ras/Raf/MEK Pathway Facilitates Hepatitis C Virus Replication via Attenuation of the Interferon-JAK-STAT Pathway

“…Many studies have demonstrated that the Ras/Raf/MEK pathway plays a role in cell proliferation (55) or neuronal differentiation (31). The relationship between this pathway and viral infection has been investigated in only a small number of studies (1,4). One study suggested that activation of this pathway was statistically correlated with HCV infection in clinics (58).…”